Bisphosphonates (BP), a class of anti-resorptive drugs, have a long history of being prescribed to treat bone disorders like osteoporosis and bone metastases in cancer patients. A side effect of anti-resorptive drugs like BPs is that long-term users are at a higher risk of developing BRONJ, which is clinically defined as exposed necrotic bone and unclosed overlaying oral mucosa for at least 8 weeks. The pathophysiology of BRONJ is highly debated most likely due to the pleiotropic effects of BPs. Recently, we have demonstrated that mice with dysfunctional osteoclasts due to BP administration manifest ONJ-like lesions about 30% of the time following dental extraction. While many groups in the field are working to understand how osteoclast dysfunction leads to BRONJ, we have revealed that diminished osteoclast function is required, but not sufficient to induce BRONJ. In order to understand what other factors are involved in BRONJ development, we have identified potential genes involved, specifically IL-36, by performing microarray analysis on biopsied tissues. We have validated the results of this assay both in vitro and in vivo, suggesting that induction of IL 36 by BP leads to suppression of extracellular matrix proteins (i.e. collagen precursors), which are required for re-epithelialization during wound healing, and this suppression may be an etiological factor in BRONJ development. The long- term goal of our research is to understand the molecular mechanisms that give rise to BRONJ and use this disease model to better understand osteomucosal wound healing. In the current study, I propose a hypothesis that IL-36 is a critical cytokine involved in ONJ development and that the IL-36 signaling pathway inhibits bone formation and wound healing via NF?B and its downstream mediators. Based on our preliminary data, I aim to: 1) Determine the mechanism by which IL-36 inhibits collagen expression; 2) Investigate the direct effects of IL- 36 signaling in vivo; and 3) Investigate IL-36 expression as a risk factor for BRONJ induction. The issue of BRONJ cannot be resolved by reducing or eliminating treatment as the underlying conditions (e.g. osteoporosis, metastatic cancer) are more severe and must be addressed. Thus, determining why BRONJ occurs, how to predict its occurrence, and establishing therapeutic treatments is critical for the patients who will experience this condition. Successful completion of the current project will address all of these issues and make significant contributions to understanding the etiopathogenesis of this painful malady. This award will prepare the trainee for an academic career as an independent researcher in wound healing and bone biology.